Increased Active Inflammation in the Colon is Not a Reliable Predictor of an Elevated Risk of Dysplasia in Patients With Primary Sclerosing Cholangitis and Ulcerative Colitis.

Although the increased risk of colorectal neoplasia in patients with both primary sclerosing cholangitis (PSC) and ulcerative colitis (UC; termed PSC-UC) is well documented, the mechanism through which concomitant PSC increases the risk of colorectal neoplasia remains unclear. Given that the risk of colorectal neoplasia in UC is positively correlated with increased histologic inflammation, this study sought to investigate whether increased histologic inflammation could be used to stratify the risk of dysplasia development in patients with PSC-UC. Twenty patients with PSC-UC and dysplasia were compared with 30 control patients with PSC-UC who had no history of neoplasia. For each patient, all surveillance biopsies were scored using a 4-point scoring system: (1) no epithelial neutrophils = 0, (2) cryptitis only = 1, (3) cryptitis plus crypt abscess in <50% of crypts = 2, and (4) crypt abscess in ≥50% of crypts, erosion, neutrophilic exudate, and/or ulceration = 3. A score was designated for each biopsy, and both mean and maximum inflammation scores were calculated from all biopsies taken during each colonoscopy. The inflammation burden score was calculated for each surveillance interval by multiplying the average maximum score between each pair of surveillance episodes by the length of the surveillance interval in years. The average scores derived from all colonoscopies for each patient were used to determine the patient's overall mean, maximum, and inflammation burden scores. In both the dysplasia and control groups, the 3 summative inflammation scores were calculated independently for the entire colon, right colon, and left colon. The dysplasia group consisted of 14 (70%) men and 6 (30%) women, with a mean age of 27 years at UC diagnosis and a long history of pancolitis (mean duration: 17 y). A total of 49 dysplastic lesions were detected in the dysplasia group, and 8 (40%) of the 20 patients had multifocal dysplasia. The majority of dysplastic lesions belonged to nonconventional subtypes (n = 28; 57%) and were located in the right colon (n = 37; 76%). Irrespective of the colon segment, there was no significant difference in the 3 summative inflammation scores between the dysplasia and control groups ( P > 0.05). However, in each group, the 3 summative inflammation scores were significantly higher in the right colon than in the left colon ( P < 0.05). In conclusion, patients with PSC-UC exhibit increased histologic inflammation in the right colon compared with the left colon, regardless of the presence of dysplasia. Although this may provide an explanation for the predominance of right-sided colorectal neoplasia in patients with PSC-UC, increased histologic inflammation does not reliably predict an elevated risk of dysplasia in patients with PSC-UC. These findings reinforce the current recommendation for annual endoscopic surveillance for all patients with PSC-UC, irrespective of the extent and severity of inflammation.

DNA content abnormality frequently develops in the right/proximal colon in patients with primary sclerosing cholangitis and inflammatory bowel disease and is highly predictive of subsequent detection of dysplasia.

AIMS: Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD, termed PSC-IBD) have a higher risk of harbouring nonconventional and/or invisible dysplasias, especially in the right/proximal colon, than those with IBD alone. We postulated that DNA content abnormality may be frequently detected in the right/proximal colon in PSC-IBD patients, even in the absence of dysplasia, and that this may predispose to progression to nonconventional and/or invisible dysplasias that are often associated with increased rates of aneuploidy and advanced neoplasia. METHODS AND RESULTS: DNA flow cytometry was performed on 96 morphologically benign colon biopsies taken throughout the colon from 25 PSC-IBD patients during the surveillance colonoscopy that preceded the next procedure that detected dysplasia. Thirty (31%) of the 96 benign colon biopsies in this dysplasia group demonstrated abnormal DNA content, with a propensity for the right/proximal colon (70%) (P < 0.001). In contrast, only one (1%) of 87 benign colon biopsies from 20 IBD patients without neoplasia (control group) demonstrated DNA content abnormality, and it was from the left colon. For analysis per patient, 48% (12 of 25) of the patients in the dysplasia group had abnormal DNA content compared with 5% (1 of 20) of the control group (P = 0.002). Of the 12 PSC-IBD patients with DNA content abnormality, invisible dysplasia was detected in 10 (83%) patients on follow-up, nine (75%) of whom had nonconventional dysplasia. CONCLUSION: PSC-IBD patients have an increased risk of developing abnormal DNA content in the right/proximal colon, predating the detection of dysplasia.

Increased Risk of Non-conventional and Invisible Dysplasias in Patients with Primary Sclerosing Cholangitis and Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Patients with primary sclerosing cholangitis and inflammatory bowel disease [termed PSC-IBD] have a higher risk of developing colorectal neoplasia than those with IBD alone. The mechanism by which concomitant PSC increases the risk of colorectal neoplasia remains unknown. Seven distinct non-conventional dysplastic subtypes have been recently described in IBD, including crypt cell dysplasia, hypermucinous dysplasia, goblet cell-deficient dysplasia, dysplasia with increased Paneth cell differentiation [DPD], sessile serrated lesion [SSL]-like dysplasia, traditional serrated adenoma [TSA]-like dysplasia, and serrated dysplasia, not otherwise specified [NOS]. Despite the lack of high-grade morphological features, crypt cell, hypermucinous, and goblet cell-deficient dysplasias often show molecular features characteristic of advanced neoplasia [i.e. aneuploidy and KRAS mutations] and are more frequently associated with advanced neoplasia than conventional dysplasia on follow-up. We aimed to characterise clinicopathological features of dysplasia found in PSC-IBD patients. METHODS: A cohort of 173 PSC-IBD patients were analysed. All dysplastic lesions were subtyped as either conventional or non-conventional dysplasia. The clinicopathological features of PSC-IBD patients with neoplasia were also compared with those of non-PSC IBD patients with neoplasia. RESULTS: There were 109 [63%] men and 64 [37%] women, with a mean age of 26 years at IBD diagnosis and a long history of IBD [mean duration: 14 years]. Ulcerative colitis was the most common IBD subtype [80%], and the majority of patients [92%] had a history of pancolitis. A total of 153 dysplastic lesions were detected in 54 [31%] patients, 35 [65%] of whom had multifocal dysplasia. One additional patient presented with colorectal cancer [CRC] without a history of dysplasia. Dysplasia was often non-conventional [n = 93; 61%], endoscopically/grossly invisible [n = 101; 66%], and right/proximal-sided [n = 90; 59%]. All seven non-conventional subtypes were identified, including 46 [30%] crypt cell dysplasia, 23 [15%] hypermucinous dysplasia, 12 [8%] goblet cell-deficient dysplasia, seven [5%] DPD, three [2%] TSA-like dysplasia, one [1%] SSL-like dysplasia, and one [1%] serrated dysplasia NOS. Follow-up information was available for 86 lesions, of which 32 [37%] were associated with subsequent detection of advanced neoplasia [high-grade dysplasia or CRC] within a mean follow-up time of 55 months. PSC-IBD patients with neoplasia were more likely to have pancolitis [98%, p = 0.039] and a longer IBD duration [mean: 17 years, p = 0.021] than those without neoplasia [89% and 12 years, respectively]. When compared with a cohort of non-PSC IBD patients with neoplasia, the PSC-IBD group with neoplasia was more often associated with non-conventional [61%, p <0.001], invisible [66%, p <0.001], and right/proximal-sided [59%, p = 0.045] dysplasias [vs 25%, 21%, and 47%, respectively, for the non-PSC IBD group]. The rate of advanced neoplasia was nearly 2-fold higher in the PSC-IBD group [37%] compared with the non-PSC IBD group [22%] [p = 0.035]. CONCLUSIONS: Nearly a third of PSC-IBD patients developed dysplasia, which is often associated with non-conventional dysplastic features, invisible endoscopic/gross appearance, right/proximal-sided colon, multifocality, and advanced neoplasia on follow-up. These findings underscore the importance of recognising these non-conventional subtypes by practising pathologists and the need for careful and frequent endoscopic surveillance, with random biopsies, in PSC-IBD patients.

Persistent or recurrent Barrett's neoplasia after an endoscopic therapy session is associated with DNA content abnormality and can be detected by DNA flow cytometric analysis of paraffin-embedded tissue.

Endoscopic therapy is currently the standard of care for the treatment of high-grade dysplasia (HGD) or intramucosal adenocarcinoma (IMC) in patients with Barrett's esophagus (BE). Visible lesions are treated with endoscopic mucosal resection (EMR), which is often coupled with radiofrequency ablation (RFA). However, endoscopic therapy may require multiple sessions (one session every 2-3 months) and does not always assure complete eradication of neoplasia. Furthermore, despite complete eradication, recurrences are not uncommon. This study assesses which potential risk factors can predict a poor response after endoscopic sessions. Forty-five BE patients who underwent at least one endoscopic session (EMR alone or ablation with or without preceding EMR) for the treatment of HGD/IMC, low-grade dysplasia (LGD), or indefinite for dysplasia (IND) were analyzed. DNA flow cytometry was performed on 82 formalin-fixed paraffin-embedded samples from the 45 patients, including 78 HGD/IMC, 2 LGD, and 2 IND. Eight non-dysplastic BE samples were used as controls. Three to four 60-micron thick sections were cut from each tissue block, and the area of HGD/IMC, LGD, or IND was manually dissected. Potential associations between clinicopathologic risk factors and persistent/recurrent HGD/IMC following each endoscopic session were examined using univariate and multivariate Cox models with frailty terms. Sixty (73%) of the 82 specimens showed abnormal DNA content (aneuploidy or elevated 4N fraction). These were all specimens with HGD/IMC (representing 77% of that group). Of these 60 HGD/IMC samples with abnormal DNA content, 42 (70%) were associated with subsequent development of persistent/recurrent HGD/IMC (n = 41) or esophageal adenocarcinoma (EAC; n = 1) within a mean follow-up time of 16 months (range: 1 month to 9.4 years). In contrast, only 6 (27%, all HGD/IMC) of the 22 remaining samples (all with normal DNA content) were associated with persistent/recurrent HGD/IMC. For outcome analysis per patient, 11 (24%) of the 45 patients developed persistent/recurrent HGD/IMC or EAC, despite multiple endoscopic sessions (mean: 3.6, range: 1-11). In a univariate Cox model, the presence of abnormal DNA content (hazard ratio [HR] = 3.8, p = 0.007), long BE segment ≥ 3 cm (HR = 3.4, p = 0.002), endoscopic nodularity (HR = 2.5, p = 0.042), and treatment with EMR alone (HR = 2.9, p = 0.006) were significantly associated with an increased risk for persistent/recurrent HGD/IMC or EAC. However, only abnormal DNA content (HR = 6.0, p = 0.003) and treatment with EMR alone (HR = 2.7, p = 0.047) remained as significant risk factors in a multivariate analysis. Age ≥ 60 years, gender, ethnicity, body mass index (BMI) ≥ 30 kg/m2, presence of hiatal hernia, and positive EMR lateral margin for neoplasia were not significant risk factors for persistent/recurrent HGD/IMC or EAC (p > 0.05). Three-month, 6-month, 1-year, 3-year, and 6-year adjusted probabilities of persistent/recurrent HGD/IMC or EAC in the setting of abnormal DNA content were 31%, 56%, 67%, 79%, and 83%, respectively. The corresponding probabilities in the setting of normal DNA content were 10%, 21%, 28%, 38%, and 43%, respectively. In conclusion, in BE patients with baseline HGD/IMC, both DNA content abnormality and treatment with EMR alone were significantly associated with persistent/recurrent HGD/IMC or EAC following each endoscopic session. DNA content abnormality as detected by DNA flow cytometry identifies HGD/IMC patients at highest risk for persistent/recurrent HGD/IMC or EAC, and it also serves as a diagnostic marker of HGD/IMC with an estimated sensitivity of 77%. The diagnosis of HGD/IMC in the setting of abnormal DNA content may warrant alternative treatment strategies as well as long-term follow-up with shorter surveillance intervals.

Gastric Intestinal Metaplasia in Mucosa Adjacent to Gastric Cancers Is Rarely Associated With the Aneuploidy That Is Characteristic of Gastric Dysplasia or Cancer.

Most gastric cancers (GCs) are thought to develop via gastric intestinal metaplasia (GIM)-dysplasia-carcinoma pathway. Patients with extensive and/or incomplete GIM have been reported to have a higher risk of GC. GIM can also display dysplasia-like cytoarchitectural atypia limited to the bases of gastric pits without surface involvement. However, only a small proportion of GIM patients will develop gastric neoplasia, and it remains questionable if GIM is a direct precursor. A cohort of 82 GC patients with GIM who underwent gastrectomy were analyzed. DNA flow cytometry was performed on 109 GIM samples (including 88 predominantly complete GIM and 21 predominantly incomplete GIM subclassified based on morphology) obtained from adjacent mucosa of the 82 GCs. Only 2 (2%) of the 109 GIM samples demonstrated aneuploidy, both from 2 minority patients (Asian and Hispanic) with limited and complete GIM and no cytoarchitectural atypia. The remaining 107 GIM samples showed mild to focally moderate basal gland (metaplastic) atypia limited to the bases of gastric pits, but they all demonstrated normal DNA content regardless of anatomic location, histologic GIM subtype, or varying degrees of basal gland atypia. In conclusion, the vast majority of the GIM samples (98%) lack the aneuploidy that is characteristic of gastric dysplasia or cancer. This indicates that aneuploidy usually occurs after the development of gastric dysplasia rather than at the stage of GIM. The finding also suggests that the presence of GIM alone may not be sufficient to suggest an increased risk for GC and that the inclusion of other high-risk features (ie, extensive GIM, dysplasia, racial minorities, and/or family history of GC in a first-degree relative) and/or aneuploidy ought to play a role in the selection of GIM patients who may warrant endoscopic surveillance. Finally, GIM with mild to focally moderate basal gland atypia is likely to represent metaplastic atypia in most cases.

Efficacy and Safety of Same-Day Discharge for Atrial Fibrillation Ablation.

OBJECTIVES: The purpose of this study was to evaluate the efficacy, health care utilization, and safety of a same-day discharge protocol. BACKGROUND: Catheter ablation of atrial fibrillation (AF) is the most common ablation performed. Increasing volumes of AF ablation are placing demands on hospital resources. In response, our institutions developed a same-day discharge protocol for AF ablation. METHODS: This was a multicenter cohort study of all patients undergoing AF ablation from 2010 to 2014 at 2 major centers. The primary efficacy outcome was the proportion of successful same-day discharges. The primary health care utilization outcome was 30-day hospital readmission for any reason. The primary safety outcome was a composite of 30-day death, stroke/transient ischemic attack or embolism, or bleeding requiring hospitalization. RESULTS: A total of 3,054 patients underwent AF ablation from 2010 to 2014 and met inclusion criteria. Same-day discharge was achieved in 79.2% (2,418 of 3,054). Hospital readmission at 30 days was 7.7% for the same-day discharge group, 10.2% for those who remained in the hospital overnight without complications (p = 0.055 for comparison with same-day discharge), and 19.5% (p < 0.001) for those who remained in the hospital with procedural complications (7.7%). Complication rates from discharge to 30 days (excluding immediate procedural complications) were 0.37% for the same-day discharge group, 0.36% (p = 0.999) for those kept overnight without complications, and 2.5% (p = 0.044) for those with initial procedural complications. CONCLUSIONS: Same-day discharge after AF ablation is feasible in the majority of patients with use of a standardized protocol. This approach was not associated with higher hospital readmission or complication rates after discharge.

A Rare Case of Carcinoid Constrictive Pericarditis.

We describe a case of atypical carcinoid heart disease. A 62-year-old woman with well-differentiated neuroendocrine tumor metastatic to the liver and lymph nodes presented with recurrent unilateral pleural effusions and lower extremity edema. Multimodality imaging and workup resulted in the diagnosis of carcinoid-related constrictive pericarditis, a rare form of carcinoid heart disease. (Level of Difficulty: Intermediate.).

One-year effectiveness study of intravitreous bevacizumab in neovascular age-related macular degeneration: a population-based retrospective cohort study.

OBJECTIVE: To assess effectiveness of intravitreous bevacizumab in a cohort of patients with neovascular age-related macular degeneration (nAMD) in British Columbia, Canada. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with new-onset AMD who completed 1 year of bevacizumab treatment. METHODS: A cohort of 4507 patients with nAMD (5174 eyes) aged 50 years and older treated on an as-needed basis with bevacizumab was followed from June 1, 2010, to May 31, 2014, and then evaluated after completing a follow-up treatment at 1 year. Descriptive statistics were used to characterize eyes treated with bevacizumab. Multivariable regression models were used to quantify visual acuity (VA) changes over time, adjusting for baseline prognostic variables. RESULTS: On average, patients received 8.6 injections (SD 2.4) per eye during the year of treatment. There was an average gain of 5.2 letters over the 1-year study period. Among eyes treated with bevacizumab, improvement in VA was greater for eyes with poorer baseline VA and for eyes receiving more injections. The odds ratio for VA at 1 year was 9.35 (95% CI 6.00-14.6) for eyes with VA 20/50-20/80 versus 20/20-20/40 and increased to 74.5 (95% CI 47.7-116.4) for eyes 20/400 or worse versus 20/20-20/40. CONCLUSION: Intravitreous bevacizumab is effective in treating nAMD, especially for eyes with poor baseline VA. Gains in VA were greatest by month 3 and were generally maintained thereafter.

NF-κB decoy oligodeoxynucleotide mitigates wear particle-associated bone loss in the murine continuous infusion model.

UNLABELLED: Total joint replacement is a cost-effective surgical procedure for patients with end-stage arthritis. Wear particle-induced chronic inflammation is associated with the development of periprosthetic osteolysis. Modulation of NF-κB signaling in macrophages, osteoclasts, and mesenchymal stem cells could potentially mitigate this disease. In the current study, we examined the effects of local delivery of decoy NF-κB oligo-deoxynucleotide (ODN) on wear particle-induced bone loss in a murine continuous femoral particle infusion model. Ultra-high molecular weight polyethylene particles (UHMWPE) with or without lipopolysaccharide (LPS) were infused via osmotic pumps into hollow titanium rods placed in the distal femur of mice for 4weeks. Particle-induced bone loss was evaluated by µCT, and immunohistochemical analysis of sections from the femur. Particle infusion alone resulted in reduced bone mineral density and trabecular bone volume fraction in the distal femur. The decoy ODN reversed the particle-associated bone volume fraction loss around the implant, irrespective of the presence of LPS. Particle-infusion with LPS increased bone mineral density in the distal femur compared with particle-infusion alone. NF-κB decoy ODN reversed or further increased the bone mineral density in the femur (3-6mm from the distal end) exposed to particles alone or particles plus LPS. NF-κB decoy ODN also inhibited macrophage infiltration and osteoclast number, but had no significant effects on osteoblast numbers in femurs exposed to wear particles and LPS. Our study suggests that targeting NF-κB activity via local delivery of decoy ODN has great potential to mitigate wear particle-induced osteolysis. STATEMENT OF SIGNIFICANCE: Total joint replacement is a cost-effective surgical procedure for patients with end-stage arthritis. Chronic inflammation is crucial for the development of wear particle-associated bone loss. Modulation of NF-κB signaling in macrophages (pro-inflammatory cells), osteoclasts (bone-resorbing cells), and osteoblasts (bone-forming cells) could potentially mitigate this disease. Here we demonstrated that local delivery of decoy NF-κB oligo-deoxynucleotide (ODN) mitigated ultra-high molecular weight polyethylene (UHMWPE) wear particle induced bone loss in a clinically relevant murine model. The protective effects of decoy ODN was associated with reduced macrophage infiltration and osteoclast activation, but had no significant effects on osteoblast numbers. Our study suggests that targeting NF-κB activity via local delivery of decoy ODN has great potential to mitigate wear particle-induced bone loss.

The effects of immunomodulation by macrophage subsets on osteogenesis in vitro.

BACKGROUND: Bone formation and remodeling are influenced by the inflammatory state of the local microenvironment. In this regard, macrophages are postulated to play a crucial role in modulating osteogenesis. However, the differential effects of macrophage subsets and their plasticity on bone formation are currently unknown. METHODS: Polarized primary murine macrophages and preosteoblastic MC3T3 cells were co-cultured to investigate the effect of non-activated M0, pro-inflammatory M1, and tissue-regenerative M2 macrophages on the osteogenic ability of MC3T3-E1 cells in vitro. Furthermore, to model the physiological transition from inflammation to tissue regeneration, M1-MC3T3 co-cultures were treated with interleukin-4 (IL-4) at different time points to modulate the M1 phenotype towards M2. Macrophage phenotypic markers were assessed by flow cytometry and enzyme-linked immunosorbent assay. A time course study of osteogenic markers at different time points was conducted: alkaline phosphatase (ALP) mRNA levels were evaluated at week 1, ALP activity and osteocalcin and osteopontin mRNA levels at week 2, and matrix mineralization and osteocalcin and osteopontin protein concentrations at week 3. Supernatant collected 72 hours after seeding or IL-4 treatment, whichever was later, was analyzed for oncostatin M, a cytokine released by macrophages that has been recognized to enhance osteogenesis. Unpaired t test or one-way ANOVA with Tukey's or Dunnett's post hoc tests were used for statistical comparison of the groups. RESULTS: Co-culture with any of the macrophage subtypes increased the osteogenic ability of MC3T3 cells as indicated by increases in ALP activity and matrix mineralization. Increased ALP activity, osteocalcin concentration, and matrix mineralization demonstrated that osteogenesis by M1-MC3T3 co-cultures was further enhanced by macrophage phenotype modulation to M2 via IL-4 treatment 72 hours after seeding. Increased oncostatin M protein concentration in untreated M1-MC3T3 co-cultures and M1-MC3T3 co-cultures treated with IL-4 at 72 hours correlated with greater ALP activity and matrix mineralization. CONCLUSIONS: These results suggest that a transient inflammatory phase is crucial for enhanced bone formation. Macrophage plasticity may offer new strategies for modulating the local inflammatory microenvironment with the aim of potentially enhancing bone repair.

Intestinal Metaplasia is Present in Most if Not All Patients Who Have Undergone Endoscopic Mucosal Resection for Esophageal Adenocarcinoma.

Barrett esophagus is presently defined in the United States by the presence of intestinal metaplasia in columnar-lined esophagus based on the premise that the risk for adenocarcinoma depends on the presence of intestinal metaplasia. Recently, arguments have been made that nonintestinalized cardiac epithelium is also at risk and should be included in the definition of Barrett esophagus, as it is in England and Japan. One of these arguments is that residual intestinal metaplasia is frequently absent around early adenocarcinomas removed by endoscopic mucosal resection (EMR). We reviewed 27 EMRs performed in 21 patients. Residual intestinal metaplasia was absent in 10/27 (37%) EMR specimens. An in-depth study of these 10 cases showed that 3 had intestinal metaplasia in a concurrent second EMR specimen, 4 had intestinal metaplasia in prior biopsy material available in our unit, and 2 had intestinal metaplasia in an esophagectomy that followed the EMR. The single patient in whom no intestinal metaplasia was found, neither in biopsies nor in EMR, and who did not undergo an esophagectomy had been under surveillance for Barrett esophagus for over 20 years. We conclude that the frequent absence of residual intestinal metaplasia around an adenocarcinoma in an EMR specimen is the result of sampling error. When evaluated in depth by looking at history, biopsies preceding the EMR, and esophagectomy following the EMR, all of these patients with adenocarcinoma had intestinal metaplasia in their columnar-lined esophagus. This indicates that intestinal metaplasia is a necessary precursor to adenocarcinoma of the esophagus.

Exposure of polyethylene particles induces interferon-γ expression in a natural killer T lymphocyte and dendritic cell coculture system in vitro: a preliminary study.

Two major issues in total joint arthroplasty are loosening of implants and osteolysis caused by wear particle-induced inflammation. Wear particles stimulate the release of pro-inflammatory cytokines, chemokines, and other inflammatory mediators from macrophages and other cells. Although the biological response of macrophages to wear debris is well established, the role of other cell types such as natural killer T lymphocytes (NKT) and dendritic cells (DCs) is limited. Here we show that ultra-high molecular weight polyethylene (UHMWPE) particles stimulate NKT cells to secrete Interferon-γ (IFN-γ); coculture with DCs further enhanced IFN-γ secretion. Furthermore, UHMWPE particles did not stimulate NKT cells to secrete IL-4, while the NKT cell natural ligand α-galactosylceramide (α-GalCer) treatment in the coculture system significantly enhanced both IFN-γ and IL-4 expression by NKT cells. Comparatively, NKT cells and/or DCs exposed to polymethylmethacrylate particles did not stimulate IFN-γ or IL-4 expression. Mouse bone marrow derived macrophage polarization by lipopolysaccharide and conditioned medium from NKT cells and/or DCs exposed to UHMWPE particles increased tumor necrosis factor-α (TNF-α), but reduced arginase-1 expression in macrophages. The current findings indicate that UHMWPE particles stimulate NKT cells/DCs to produce pro-inflammatory cytokines; this pathway is a novel therapeutic target to mitigate wear particle induced peri-prosthetic osteolysis.

NF-κB decoy oligodeoxynucleotide enhanced osteogenesis in mesenchymal stem cells exposed to polyethylene particle.

Excessive generation of wear particles after total joint replacement may lead to local inflammation and periprosthetic osteolysis. Modulation of the key transcription factor NF-κB in immune cells could potentially mitigate the osteolytic process. We previously showed that local delivery of ultrahigh-molecular-weight polyethylene (UHMWPE) particles recruited osteoprogenitor cells and reduced osteolysis. However, the biological effects of modulating the NF-κB signaling pathway on osteoprogenitor/mesenchymal stem cells (MSCs) remain unclear. Here we showed that decoy oligodeoxynucleotide (ODN) increased cell viability when primary murine MSCs were exposed to UHMWPE particles, but had no effects on cellular apoptosis. Decoy ODN increased transforming growth factor-beta 1 (TGF-ß1) and osteoprotegerin (OPG) in MSCs exposed to UHMWPE particles. Mechanistic studies showed that decoy ODN upregulated OPG expression through a TGF-ß1-dependent pathway. By measuring the alkaline phosphatase activity, osteocalcin levels, Runx2 and osteopontin expression, and performing a bone mineralization assay, we found that decoy ODN increased MSC osteogenic ability when the cells were exposed to UHMWPE particles. Furthermore, the cellular response to decoy ODN and UHMWPE particles with regard to cell phenotype, cell viability, and osteogenic ability was confirmed using primary human MSCs. Our results suggest that modulation of wear particle-induced inflammation by NF-κB decoy ODN had no adverse effects on MSCs and may potentially further mitigate periprosthetic osteolysis by protecting MSC viability and osteogenic ability.

Generational sex work and HIV risk among Indigenous women in a street-based urban Canadian setting.

In Canada, Indigenous women are over-represented among new HIV infections and street-based sex workers. Scholars suggest that Aboriginal women's HIV risk stems from intergenerational effects of colonisation and racial policies. This research examined generational sex work involvement among Aboriginal and non-Aboriginal women and the effect on risk for HIV acquisition. The sample included 225 women in street-based sex work and enrolled in a community-based prospective cohort, in partnership with local sex work and Aboriginal community partners. Bivariate and multivariate logistic regression modeled an independent relationship between Aboriginal ancestry and generational sex work and the impact of generational sex work on HIV infection among Aboriginal sex workers. Aboriginal women (48%) were more likely to be HIV-positive, with 34% living with HIV compared to 24% non-Aboriginal women. In multivariate logistic regression model, Aboriginal women remained three times more likely to experience generational sex work (AOR:2.97; 95%CI:1.5,5.8). Generational sex work was significantly associated with HIV (AOR = 3.01, 95%CI: 1.67-4.58) in a confounder model restricted to Aboriginal women. High prevalence of generational sex work among Aboriginal women and three-fold increased risk for HIV infection are concerning. Policy reforms and community-based, culturally safe and trauma informed HIV-prevention initiatives are required for Indigenous sex workers.

Sex-for-Crack exchanges: associations with risky sexual and drug use niches in an urban Canadian city.

BACKGROUND: While crack cocaine has been associated with elevated sexual risks and transmission of HIV/STIs, particularly in the context of street-based sex work, few empirical studies have examined correlates of direct sex-for-crack exchanges. This study longitudinally examined the correlates of sex-for-crack exchanges and associated effects on sexual risk outcomes among street-based female sex workers (SW) who use drugs in Vancouver, Canada. METHODS: Data were drawn from a prospective cohort of street-based SWs (2006-2008), restricted to those who smoke crack cocaine. Multivariable generalized estimating equations (GEE) were employed to examine the correlates of exchanging sex for crack. A confounding model using GEE quasi-Poisson regression modeled the independent effect of exchanging sex for crack on number of clients/week. RESULTS: Of 206 SWs, 101 (49%) reported sex-for-crack exchanges over 18 months of follow-up. In multivariable GEE analyses, sharing a crack pipe with a client (aOR = 1.98; 95%CI: 1.27-3.08) and smoking crack in a group of strangers (e.g., in an alley or crackhouse) (aOR = 1.70; 95% CI: 1.13-2.58) were independently correlated with sex-for-crack exchanges. In our confounding model, exchanging sex for crack (aIRR = 1.34; 95% CI: 1.07-1.69) remained significantly associated with servicing a greater number (>10) of clients/week. CONCLUSIONS: These findings reveal elevated sexual- and drug- risk patterns among those who exchange sex for crack. The physical and social environment featured prominently in our results as a driver of sex-for-crack exchanges, highlighting the need for gender-sensitive multilevel approaches to harm reduction, STI and HIV prevention that address SWs' environment, individual level factors, and the interplay between them.

Injection drug use and HIV antiretroviral therapy discontinuation in a Canadian setting.

We investigated whether drug-related behaviors predicted antiretroviral therapy (ART) discontinuation among a cohort of injection drug users (IDU) in a Canadian setting. Cox regression analyses were used to investigate the impact of drug use patterns on rates of ART discontinuation among a sample of HIV-positive IDU in Vancouver, Canada between May 1996 and April 2008. In total, 408 HIV-positive IDU initiated ART during the study period, among whom 257 (63.0%) discontinued ART at least once. Rates of ART discontinuation were not significantly elevated among those who reported ongoing injection of heroin, cocaine, or other illicit drugs in comparison to those who reported not injecting drugs. However, public drug use was significantly predictive of ART discontinuation. Our findings may contribute to a reconsideration of the role of active drug use in determining retention in ART programs among IDU.

Improved survival associated with pre-hospital triage strategy in a large regional ST-segment elevation myocardial infarction program.

OBJECTIVES: This study sought to compare the 1-year survival of patients diagnosed with ST-segment elevation myocardial infarction (STEMI) and transferred via pre-hospital triage strategy for primary percutaneous coronary intervention (PCI) with those transferred via inter-hospital transfer within a large suburban region in Canada. BACKGROUND: Primary angioplasty is the preferred therapy for STEMI if it is done within 90 min of door-to-balloon time by an experienced team in a high-volume center. METHODS: Patients identified to have STEMI on the ambulances equipped with electrocardiography bypassed the local hospitals and were sent directly to the PCI center, whereas other patients that were picked up by ambulances without electrocardiographic equipment were transported to the local hospitals where the diagnosis of STEMI was made and were re-routed to the PCI center. Patient demographic data, clinical presentation, procedural data, in-hospital course, and vital statistics were prospectively recorded in a provincial cardiac registry. RESULTS: A total of 167 patients were brought into the PCI center via pre-hospital triage strategy, and 427 patients were brought in via inter-hospital transfer during a 2-year study period. Baseline demographic data, infarct location, cardiovascular history, and hemodynamic status were similar between the 2 groups. When compared with the inter-hospital transfer group, a significantly higher proportion of pre-hospital triaged patients achieved the 90-min door-to-balloon time benchmark (80.4% vs. 8.7%, p < 0.001) and post-procedural Thrombolysis In Myocardial Infarction flow grade 3 after the emergency procedure (97.6% vs. 91.4%, p = 0.02). In addition, the pre-hospital triage strategy was associated with a significantly lower 30-day (5.4% vs. 13.3%, p = 0.006) and 1-year (6.6% vs. 17.5%, p = 0.019) mortality. Pre-hospital triage was an independent predictor for survival at 1 year (hazard ratio: 0.37, 95% confidence interval: 0.18 to 0.75, p = 0.006). CONCLUSIONS: Pre-hospital triage strategy was associated with improved survival rate in patients undergoing primary PCI in a regional STEMI program.

Factors associated with difficulty accessing crack cocaine pipes in a Canadian setting.

INTRODUCTION AND AIMS: Crack cocaine pipe sharing is associated with various health-related harms, including hepatitis C transmission. Although difficulty accessing crack pipes has been found to predict pipe sharing, little is known about the factors that limit pipe access in settings where pipes are provided at no cost, albeit in limited capacity. Therefore, we investigated crack pipe access among people who use drugs in Vancouver, Canada. DESIGN AND METHODS: Data were collected through two Canadian prospective cohort studies. Generalised estimating equations with logit link for binary outcomes were used to identify factors associated with difficulty accessing crack pipes. RESULTS: Among 914 participants who reported using crack cocaine, 33% reported difficulty accessing crack pipes. In multivariate analyses, factors independently associated with difficulty accessing crack pipes included: sex work involvement [adjusted odds ratio (AOR) = 1.57; 95% confidence interval (CI): 1.03-2.39], having shared a crack pipe (AOR = 1.69; 95% CI: 1.32-2.16), police presence where one buys/uses drugs (AOR = 1.47; 95% CI: 1.10-1.95), difficulty accessing services (AOR = 1.74; 95% CI: 1.31-2.32) and health problems associated with crack use (AOR = 1.37; 95% CI: 1.04-1.79). Reasons given for difficulty accessing pipes included sources being closed (48.2%) and no one around selling pipes (18.1%). DISCUSSION AND CONCLUSIONS: A substantial proportion of people who smoke crack cocaine report difficulty accessing crack pipes in a setting where pipes are available at no cost but in limited quantity. These findings indicate the need for enhanced efforts to distribute crack pipes and address barriers to pipe access.

Young age predicts poor antiretroviral adherence and viral load suppression among injection drug users.

Previous studies of adherence to antiretroviral therapy (ART) for HIV among young injection drug users (IDU) have been limited because financial barriers to care disproportionately affect youth, thus confounding results. This study examines adherence among IDU in a unique setting where all medical care is provided free-of-charge. From May 1996 to April 2008, we followed a prospective cohort of 545 HIV-positive IDU of 18 years of age or older in Vancouver, Canada. Using generalized estimating equations (GEE), we studied the association between age and adherence (obtaining ART≥95% of the prescribed time), controlling for potential confounders. Using Cox proportional hazards regression, we also studied the effect of age on time to viral load suppression (<500 copies per milliliter), and examined adherence as a mediating variable. Five hundred forty-five participants were followed for a median of 23.8 months (interquartile range [IQR]=8.5-91.6 months). Odds of adherence were significantly lower among younger IDU (adjusted odds ratio [AOR]=0.76 per 10 years younger; 95% confidence interval [CI], 0.65-0.89). Younger IDU were also less likely to achieve viral load suppression (adjusted hazard ratio [AHR]=0.75 per 10 years younger; 95% CI, 0.64-0.88). Adding adherence to the model eliminated this association with age, supporting the role of adherence as a mediating variable. Despite absence of financial barriers, younger IDU remain less likely to adhere to ART, resulting in inferior viral load suppression. Interventions should carefully address the unique needs of young HIV-positive IDU.